NM_004656.4:c.126T>C

BAP1 · NP_004647.1:p.(Pro42=) · NM_004656.4

GRCh37: chr3:52442619 A>G · GRCh38: chr3:52408603 A>G

Gene: BAP1 Transcript: NM_004656.4

Final call

VUS

PM2 supporting

Variant details

Gene

BAP1

Transcript

NM_004656.4

Protein

NP_004647.1:p.(Pro42=)

gnomAD AF

3.1075742772403747e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): gnomAD v4.1 total AF 3.10757e-06 (5/1,608,972 alleles) with zero homozygotes, absent from gnomAD v2.1, more than 30-fold below the 0.1% pathogenic-support threshold.

Variant of Uncertain Significance: the single supporting pathogenic criterion (PM2) satisfies no ACMG/AMP 2015 Pathogenic or Benign combination threshold.

Final determination: Generic ACMG/AMP 2015 fallback: with only one supporting pathogenic criterion (PM2) applied and no benign criteria met, no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold is satisfied, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: this synonymous change (p.Pro42=) triggers no null-variant mechanism such as nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: no altered amino acid exists to compare, because the change is synonymous (p.Pro42=).	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no de novo occurrence or parental testing for this variant is reported in any ClinVar submission or publication.	clinvar PMID:25394175 PMID:27748099 PMID:28492532
PS3	Not assessed	Not assessed: no functional assay evidence for this variant was available in any source.	spliceai PMID:25394175 PMID:27748099 PMID:28492532
PS4	Not assessed	Not assessed: no case-control or cohort prevalence data for this variant exists; only population frequencies were available.	gnomad_v4 gnomad_v2
PM1	N/A	Not applicable: no altered residue exists to evaluate for mutational hotspot or critical-domain membership in this synonymous change.	generic_acmg_combination_rules
PM2	Met	Met (Supporting): present in gnomAD v4.1 at total AF 3.10757e-06 (5/1,608,972 alleles) and absent from gnomAD v2.1, more than 30-fold below the 0.1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	N/A	Not applicable: BAP1 tumor predisposition syndrome is autosomal dominant, so the recessive-disorder trans requirement of PM3 does not apply.	generic_acmg_combination_rules pvs1_gene_context clinvar
PM4	N/A	Not applicable: this synonymous change produces no protein-length alteration for PM4 to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a different pathogenic missense change.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo occurrence of this variant is reported in any source, with or without confirmed parentage.	clinvar PMID:25394175 PMID:27748099 PMID:28492532
PP1	Not assessed	Not assessed: no co-segregation data in affected family members exists for this variant in any ClinVar submission or publication.	clinvar PMID:25394175 PMID:27748099 PMID:28492532
PP2	N/A	Not applicable: this synonymous change produces no missense variant to evaluate against the gene's missense-constraint profile.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta score 0.01 versus the 0.2 recommended splice-impact threshold, and no other predictor indicates a deleterious effect.	spliceai
PP4	Not assessed	Not assessed: no proband phenotype or family history data was available to evaluate phenotype specificity.
PP5	Not met	Not met: the ClinVar record has zero expert-panel submissions, so no expert-panel Pathogenic/Likely pathogenic classification exists for this variant.	clinvar
BA1	Not met	Not met: highest observed allele frequency 0.00267% (African/African American) versus the 1% stand-alone benign threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: maximum allele frequency 0.00267% versus the 0.3% threshold for this rare dominant cancer predisposition syndrome.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	Not met	Not met: gnomAD v4.1 reports zero homozygotes (0/1,608,972 alleles) and no healthy-adult enrichment was observed.	gnomad_v4 generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no well-established functional study of this variant was available; the SpliceAI prediction is in-silico, not a functional assay.	spliceai PMID:25394175 PMID:27748099 PMID:28492532
BS4	Not assessed	Not assessed: no family segregation data of any kind exists to evaluate non-segregation.	clinvar PMID:25394175 PMID:27748099 PMID:28492532
BP1	N/A	Not applicable: this synonymous change produces no missense variant to evaluate in a gene whose disease mechanism is truncation.	generic_acmg_combination_rules
BP2	Not met	Not met: no source reports this variant in trans or cis with a pathogenic variant.	generic_acmg_combination_rules clinvar PMID:25394175 PMID:27748099 PMID:28492532
BP3	N/A	Not applicable: this synonymous change produces no in-frame length alteration in a repetitive region to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: only one line of computational evidence is available (SpliceAI delta 0.01), while BP4 requires multiple concordant lines.	spliceai
BP5	Not assessed	Not assessed: no case-level data exists to identify an alternate molecular basis for disease.
BP6	Not met	Not met: the ClinVar record has zero expert-panel submissions, so no expert-panel Benign/Likely benign classification exists for this variant.	clinvar
BP7	Not assessed	Not assessed: no splice impact is predicted (SpliceAI delta 0.01), but the required nucleotide-conservation data was unavailable.	spliceai pvs1_variant_assessment

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